Control of arthropods in animals

ABSTRACT

A method of controlling parasites in or on an animal comprising administering to the animal a parasiticidally effective, substantially non-emetic 1-arylpyrazole.

[0001] The present invention relates to a method of control of parasitesin animals, compositions comprising a compound effective for the saidcontrol and compounds effective against parasites.

[0002] It is generally a goal of agronomists and veterinarians topossess sufficient means to control pests, particularly arthropods, whenthey attempt to invade or attack mammals, particularly domestic animalsand/or livestock. A classical method of controlling such pests has beenthe use of topical and/or systemic pesticides on or in the domesticanimal which is being attacked. Generally effective treatments includethe oral administration of insect growth regulators, such as lufenuron,or antihelminth compounds such as an ivermectin or an avermectin, or thetopical application of the insecticide fipronil. It is advantageous toapply pesticides to animals in oral form so as to prevent the possiblecontamination of humans or the surrounding environment. It is an objectof the present invention to provide new pesticides which may be used indomestic animals.

[0003] Another object of the invention is to provide safer pesticidesfor domestic animals.

[0004] Another object of the invention is to provide new pesticides fordomestic animals that may be used in lower doses than existingpesticides.

[0005] These objects are met in whole or in part by the presentinvention.

[0006] U.S. Pat. No. 5,079,370, EP-A 0,846,686, WO 98/24769 and WO97/28126 disclose the use of arylpyrazoles as parasiticidal agents.However, these references are completely silent on the problem that antiparasitical agents often elicit emesis in the animal to be protected orcured from the parasites.

[0007] The present invention provides a method of controlling parasitesin or on an animal comprising administering, preferably orally, to theanimal a parasiticidally effective, substantially non-emetic amount of a1-arylpyrazole of formula (I):

[0008] wherein:

[0009] R₂₀₁ is cyano, C(O)alkyl, C(S)NH₂, C(NH)OR₂₀₃, C(NH)SR₂₀₃, alkyl,C(═NOH)NH₂, C(═NNH₂)NH₂, C(O)NH₂, C(O)NHR₂₀₅, C(O)NR₂₀₅R₂₀₆, haloalkylor heterocyclyl from the group:

[0010] optionally substituted by R₂₀₃;

[0011] R₂₀₂ is S(O)_(h)R₂₀₃, C₂-C₆ alkenyl, C₂-C₆ haloalkenyl,cycloalkyl, halocycloalkyl, cycloalkyl-alkyl , C₂-C₆ alkynyl, nitro orimidazol-2-yl optionally substituted by alkyl, alkoxy, haloalkyl,halogen, cyano and/or nitro;

[0012] R₂₀₃, is alkyl or haloalkyl;

[0013] R₂₀₄ is —OH, R₂₀₅O—, HC(O)O—, R₂₀₅C(O)O—, R₂₀₅OC(O)O—, NH₂C(O)O—,R₂₀₅NHC(O)O—, R₂₀₅R₂₀₆NC(O)O—, R₂₀₅S(O)_(n)C(O)O—, R₂₀₆SO₂O—,aryl-SO₂O—, (C₄-C₇)-oxacycloalkyloxy, R₂₀₅R₂₀₆N—C(NR₂₀₅)—O—,R₂₀₅R₂₀₆N—C(NH)—O—, R₂₀₅NH—C(NR₂₀₅)—O—, R₂₀₅NH—C(NH)—O—, R₂₀₅N═CH—O—,R₂₀₅N═C(R₂₀₆)—O—, R₂₀₅NH—C(S)—O—, R₂₀₅R₂₀₆N—C(S)—O—;

[0014] R₂₀₅ is alkyl, haloalkyl, cycloalkyl, halocycloalkyl,alkoxyalkyl, haloalkoxyalkyl, adamantyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, haloalkylaminoalkyl, di(haloalkyl)aminoalkyl, aryloptionally substituted, hetaryl optionally substituted, arylalkyloptionally substituted, hetarylalkyl optionally substituted, C₂-C₆alkenyl, C₂-C₆ alkinyl;

[0015] R₂₀₆ is alkyl, haloalkyl, cycloalkyl, halocycloalkyl,alkoxyalkyl, haloalkoxyalkyl, aryl optionally substituted, hetaryloptionally substituted, arylalkyl optionally substituted, hetarylalkyloptionally substituted;

[0016] or R₂₀₅ and R₂₀₆ may form together with the nitrogen to whichthey are attached a 3 to 7 membered ring which additionally may containone or more heteroatoms selected from nitrogen, oxygen and sulfur;

[0017] X₁ is selected from nitrogen and C—R₂₁₂;

[0018] R₂₁₁, R₂₁₂ are independently selected from halogen, hydrogen, CN,C₁-C₃ alkyl and NO₂;

[0019] R₂₁₃ is selected from halogen, haloalkyl, haloalkoxy,—S(O)_(k)CF₃, and —SF₅ or forms a ring with R₂₁₄;

[0020] R₂₁₄ is hydrogen or may constitute together with R₂₁₃ a group ofOCF₂O, CF₂OCF₂, CF₂OCF₂O and CF₂CF₂O, which forms together with thecarbons they are attached to a five to six membered ring; and

[0021] h, k and n are independently selected from 0, 1, and 2;

[0022] and veterinarily acceptable salts thereof.

[0023] By the term “veterinariiy acceptable salts” is meant salts theanions of which are known and accepted in the art for the formation ofsalts for veterinary use. Suitable acid addition salts, e.g. formed bycompounds of formula (I) containing a basic nitrogen atom, e.g. an aminogroup, include salts with inorganic acids, for example hydrochlorides,sulphates, phosphates and nitrates and salts with organic acids forexample acetic acid.

[0024] When R₂₀₄ is OH the pyrazole structure can also be exhibited byits tautomeric form as pyrazolon structure.

[0025] Unless otherwise specified, alkyl and alkoxy groups are straightchain or branched and are generally lower alkyl and alkoxy groups, thatis having from one to six carbon atoms, preferably from one to fourcarbon atoms. Generally, the haloalkyl, haloalkoxy and haloalkylaminogroups have from one to four carbon atoms. Halogen means F, Cl, Br, andI, preferably F and Cl. The haloalkyl and haloalkoxy and haloalkylaminogroups can bear one or more halogen atoms; preferred groups of this typeinclude —CF₃ and —OCF₃. Cycloalkyl groups generally have from 3 to 6carbon atoms, preferably from 3 to 5 carbon atoms and may be substitutedby one or more halogen atoms. Preferably in compounds of formula (I),alkyl groups are generally substituted by from one to five halogenatoms, preferably from one to three halogen atoms. Chlorine and fluorineatoms are preferred.

[0026] In compounds of formula (I) the following examples of radicalsare provided:

[0027] An example of cycloalkylalkyl is cyclopropylmethyl;

[0028] an example of cycloalkoxy is cyclopropyloxy; and

[0029] an example of alkoxyalkyl is CH₃OCH₂—.

[0030] Generally, in dialkylamino or di(haloalkyl)amino radicals, thealkyl and haloalkyl groups on nitrogen may be chosen independently ofone another.

[0031] Generally, the term “aryl” means a carbocyclic aromatic radicalhaving preferably 6 to 14, in particular 6 to 12, carbon atoms, forexample phenyl, naphthyl or biphenylyl, preferably phenyl;

[0032] the term “heterocyclyl” preferably a hetaryl or heteroaliphaticring system, “hetaryl” preferably being understood as meaning an arylradical in which at least one CH group is replaced by N and/or at leasttwo adjacent CH groups are replaced by S, NH or O, for example a radicalof thiophene, furan, pyrrole, thiazole, oxazole, imidazole, isothiazole,isoxazole, pyrazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole,1,3,4-triazole, 1,2,4-oxadiazole, 1,2,4-thiadiazole, 1,2,4-triazole,1,2,3-triazole, 1,2,3,4-tetrazole, benzo[b]thiophene, benzo[b]furan,indole, benzo[c]thiophene, benzo[c]furan, isoindole, benzoxazole,benzothiazole, benzimidazole, benzisoxazole, benzisothiazole,benzopyrazole, benzothiadiazole, benzotriazole, dibenzofuran,dibenzothiophene, carbazole, pyridine, pyrazine, pyrimidine, pyridazine,1,3,5-triazine, 1,2,4triazine, 1,2,4,5-triazine, quinoline,isoquinoline, quinoxaline, quinazoline, cinnoline, 1,8-naphthyridine,1,5-naphthyridine, 1,6-naphthyridine, 1,7-naphthyridine, phthalazine,pyridopyrimidine, purine, pteridine or 4H-quinolizine;

[0033] and the term “heteroaliphatic ring system” preferably a(C₃-C₈)cycloalkyl radical in which at least one carbon unit is replacedby O, S or a group NR′ and R′ is hydrogen, (C₁-C₄)alkyl,(C₁-C₄)alkanoyl, (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkylsulfonyl,(C₁-C₄)alkoxy or aryl;

[0034] The substituents with which the various aliphatic,cycloaliphatic, aromatic and heterocyclic ring systems can be providedare, for example, halogen, nitro, cyano, di-(C₁-C₄)alkylamino,(C₁-C₄)alkyl, (C₁-C₈)cycloalkyl, (C₁-C₄)trialkylsilyl, (C₁-C₄)alkoxy,(C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₂)alkoxy-[CH₂CH₂O]_(0,1,2)-ethoxy,(C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl, phenyl,benzyl, phenoxy, halophenoxy, (C₁-C₄)alkylphenoxy, (C₁-C₄)alkoxyphenoxy,phenylthio, heterocyclyl, heterocyclylthio or heterocyclyloxy, it beingpossible for one or more, in the case of fluorine also up to the maximumnumber of, hydrogen atoms in the alkyl radicals and the radicals derivedtherefrom to be replaced by halogen, preferably chlorine or fluorine,where, in the event that these substituents are (C₁-C₄)alkyl, they mayalso be linked cyclically and where one or two aliphatic carbon units inthese fused ring systems, such as, for example, the indane, di-, tetra-or decahydronaphthyl or benzocycloheptane system, may be replaced byheteroatom units such as oxygen or sulfur and where one or more, in thecase of fluorine also up to the maximum number of, hydrogen atoms on thealiphatic carbon atom units can be replaced by halogen or (C₁-C₄)alkyl.

[0035] It is also to be understood that enantiomeric and diastereomericforms of the compounds of formulae (I) and salts thereof are embraced bythe present invention.

[0036] By the term non-emetic is meant a compound that does notgenerally elicit emesis from the animal when a protective, preventativeor cleaning dose is administered to the animal. By the term emesis ismeant vomiting. Generally an emetic substance elicits the said emesis inless than 24 hours after administration, preferably less than 8 hours,more preferably less than 2 hours. Generally when the compounds of theinvention are administered to a population of animals, more than 70% ofthe animals are free of emesis, preferably more than 80%, mostpreferably more than 90%.

[0037] Preferred compounds of the formula (I) are those wherein:

[0038] R₂₀₁ is cyano, C(O)alkyl, C(S)NH₂, alkyl, C(═NOH)NH₂ orC(═NNH₂)NH₂;

[0039] R₂₀₂ is S(O)_(h)R₂O₃, C₂-C₃ alkenyl, C₂-C₃ haloalkenyl,cycloalkyl, halocycloalkyl, cycloalkyl-alkyl , C₂-C₃ alkynyl;

[0040] R₂₀₃ is alkyl or haloalkyl;

[0041] R₂₀₄ is —OH, R₂₀₅O—, HC(O)O—, R₂₀₅C(O)O—, R₂₀₅OC(O)O—, NH₂C(O)O—,R₂₀₅NHC(O)O—,

[0042] R₂₀₅R₂₀₆NC(O)O—, R₂₀₅S(O)_(n)C(O)O—;

[0043] R₂₀₅ is alkyl, haloalkyl, cycloalkyl, halocycloalkyl,alkoxyalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, haloalkylaminoalkyl, di(haloalkyl)aminoalkyl,

[0044] R₂₀₆ is alkyl, haloalkyl, cycloalkyl, halocycloalkyl,alkoxyalkyl, haloalkoxyalkyl, or R₂₀₅ and R₂₀₆ may form together withthe nitrogen to which they are attached a 3 to 7 membered ring whichadditionally may contain one or more heteroatoms selected from nitrogen,oxygen and sulfur;

[0045] X₁ is selected from nitrogen and C—R₂₁₂;

[0046] R₂₁₁, R₂₁₂ are independently selected from halogen, hydrogen, CN,and NO₂;

[0047] R₂₁₃ is selected from halogen, haloalkyl, haloalkoxy,—S(O)_(k)CF₃, and —SF₅

[0048] R₂₁₄ is hydrogen; and

[0049] h, k and n are independently selected from 0, 1, and 2.

[0050] Further compounds of formula (I) which are preferred according tothe present intention are those wherein:

[0051] R₂₀₁ is cyano;

[0052] R₂₀₂ is S(O)_(h)R₂O₃;

[0053] R₂₀₃ is alkyl or haloalkyl;

[0054] R₂₀₄ is OH or R₂₀₅O;

[0055] X₁ is selected from nitrogen and C—R₂₁₂;

[0056] R₂₁₁ and R₂₁₂ are independently selected from halogen, hydrogen,CN and NO₂;

[0057] R₂₁₃ is selected from halogen, haloalkyl, haloalkoxy,—S(O)_(k)CF₃, and —SF₅; and

[0058] h and k are independently selected from 0, 1, and 2.

[0059] The compounds of formula (I) of the present invention preferablyhave one or more of the following features:

[0060] R₂₀₁ is cyano;

[0061] R₂₀₃ is halomethyl, preferably CF₃;

[0062] R₂₁₁, and R₂₁₂are independently halogen;

[0063] X₁ is C—R₂₁₂;

[0064] R₂₁₃ is haloalkyl, haloalkoxy or —SF₅; or

[0065] h is 0 or 1, or 2.

[0066] A further embodiment of the invention includes compounds of theformula (I), with the proviso that if R₂₀₁ is CN and R₂₀₂ isS(O)_(h)R₂₀₃ then R₂₀₄ is not R₂₀₅O or R₂₀₅R₂₀₆N—C(O)—O—.

[0067] In another aspect of the present invention there is provided amethod of controlling parasites in or on an animal by administering tothe animal an 1-arylpyrazole of formula (II):

[0068] wherein:

[0069] R₂₁ is cyano, C(═S)NH₂, C(═NOH)NH₂ or C(═NNH₂)NH₂;

[0070] R₂₂ is S(O)_(m)R₂₃;

[0071] R₂₃ is alkyl or haloalkyl;

[0072] R₂₄ is OH, HC(O)O—, R₂₅C(O)O—, R₂₅OC(O)O—, R₂₆R₂₅—N—C(O)—O— orR₂₅S(O)_(n)C(O)O—;

[0073] R₂₅ is alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxyalkyl,haloalkoxyalkyl, adamantyl, adamantyl, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, haloalkylaminoalkyl, di(haloalkyi)aminoalkyl, aryloptionally substituted, hetaryl optionally substituted, arylalkyloptionally substituted, hetarylalkyl optionally substituted, C₂-C₆alkenyl, C₂-C₆ alkinyl;

[0074] or two groups R₂₅ may form together with the nitrogen to whichthey are attached a 3 to 7 membered ring which additionally may containone or more heteroatoms selected from nitrogen, oxygen and sulfur;

[0075] X is selected from nitrogen and C—R₃₂;

[0076] R₃₁ and R₃₂ are independently selected from halogen, hydrogen,CN, C₁-C₃ alkyl and NO₂;

[0077] R₃₃ is selected from halogen, haloalkyl, haloalkoxy,—S(O)_(r)CF₃, and —SF₅ or forms a ring together with R₃₄;

[0078] R₃₄ is hydrogen or may constitute together with R₂₁₃ a group ofOCF₂O, CF₂OCF₂, CF₂OCF₂O and CF₂CF₂O, which forms together with thecarbons they are attached to a five to six membered ring;

[0079] m is 0, 1 or 2;

[0080] r is selected from 0, 1, and 2;

[0081] and veterinarily acceptable salts thereof;

[0082] provided that if R₂₁ is cyano then R₂₄ is not R₂₅R₂₅—N—C(O)—O—.

[0083] Preferred are compounds of formula (II),

[0084] wherein:

[0085] R₂₁ is cyano, C(═S)NH₂, C(═NOH)NH₂ or C(═NNH₂)NH₂;

[0086] R₂₂ is S(O)_(m)R₂₃;

[0087] R₂₃ is alkyl or haloalkyl;

[0088] R₂₄ is OH, HC(O)O—, R₂₅C(O)O—, R₂₅OC(O)O— or R₂₅S(O)_(n)C(O)O—;

[0089] R₂₅ is alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxyalkyl,haloalkoxyalkyl;

[0090] X is selected from nitrogen and C—R₃₂;

[0091] R₃₁ and R₃₂ are independently selected from halogen, hydrogen,CN, C₁-C₃ alkyl and NO₂;

[0092] R₃₃ is selected from halogen, haloalkyl, haloalkoxy,—S(O)_(r)CF₃, and —SF₅

[0093] In another aspect of the present invention there is provided acompound of formula (II) or salt thereof as hereinbefore described withthe proviso that the compound is not1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthio-5-hydroxypyrazole.

[0094] A further preferred class of compounds of formula (II) are thosewherein:

[0095] R₂₁ is cyano;

[0096] R₂₂ is S(O)_(m)R₂₃;

[0097] R₂₃ is haloalkyl, preferably CF₃;

[0098] R₂₄ is OH;

[0099] X is selected from nitrogen and C—R₃₂;

[0100] R₃₁ and R₃₂ are independently selected from halogen,

[0101] R₃₃ is selected from halogen, haloalkyl, haloalkoxy, S(O)_(r)CF₃,and —SF₅;

[0102] m and r are independently selected from 0, 1, and 2 with theproviso that the compound is not1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthio-5-hydroxypyrazole.

[0103] In a further aspect of the invention the following groups ofcompounds are provided: Compounds of the formula (I), wherein

[0104] R₂₀₁ is C(O)NH₂, C(O)NHR₂₀₅, C(O)NR₂₀₅R₂₀₆, C(O)N═S(R₂₀₃)₂,haloalkyl or heterocyclyl from the group:

[0105] optionally substituted by R₂₀₃.

[0106] Compounds of the formula (I), wherein

[0107] R₂₀₂ is nitro or imidazol-2-yl optionally substituted by alkyl,alkoxy, haloalkyl, halogen, cyano, nitro.

[0108] Compounds of the formula (I), wherein

[0109] R₂₀₄ is R₂₀₆SO₂O—, aryl-SO₂O—, (C₄-C₇)-oxacycloalkyloxy,R₂₀₅R₂₀₆N—C(NR₂₀₅)—O—, R₂₀₅R₂₀₆N—C(NH)—O—, R₂₀₅NH—C(NR₂₀₅)—O—,R₂₀₅NH—C(NH)—O—, R₂₀₅N═CH—O—, R₂₀₅N═C(R₂₀₆)—O—, R₂₀₅NH—C(S)—O—,R₂₀₅R₂₀₆N—C(S)—O—.

[0110] Compounds of the formula (I), wherein

[0111] R₂₁₄ constitute together with R₂₁₃ a group of OCF₂O, CF₂OCF₂,CF₂OCF₂O and CF₂CF₂O, which forms together with the carbons they areattached to a five to six membered ring.

[0112] The compounds1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluromethylsulfinyl-5-hydroxypyrazoleand1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluromethylsulfonyl-5-hydroxypyrazoleare highly preferred compounds according to the invention.

[0113] The following compounds of formula (I) are preferred according tothe present invention as listed in Tables 1 to 3. The Compound Numbersare for identification purposes only. The following symbols are herebydefined: Me means methyl; Et means ethyl; n-Pr means n-propyl; i-Prmeans isopropyl; n-Bu means n-Butyl; and Ph means Phenyl. TABLE 1Compounds of formula (I) wherein R₂₀₁ is cyano; R₂₀₂ is SCF₃; R₂₁₁ isCl, X₁ is C—Cl, R₂₁₄ is H and R₂₁₃ is CF₃ or SF₅. Phys. data: meltingpoint (° C.) or NMR (¹H, ¹⁹F-NMR, ppm) Compound Compound Number Number(R₂₁₃═CF₃) (R₂₁₃═SF₅) R₂₀₄ Phys. data  1-1  1-2 OH 19F: −44.9 −63.8 ppm 2-1  2-2 OMe mp. 83  3-1  3-2 OEt mp. 105  4-1  4-2 OPr  5-1  5-2O-i-Pr  6-1  6-2 O-n-Bu  7-1  7-2 OCH₂OMe  8-1  8-2 OCH₂CH₂OMe  9-1  9-2OCH₂OEt 10-1 10-2 OCH₂CH₂OEt 11-1 11-2 OC(O)Me 12-1 12-2 OC(O)Et 13-113-2 OC(O)n-Pr 14-1 14-2 OC(O)H 15-1 15-2 OC(O)NH₂ 16-1 16-2 OC(O)NHMe17-1 17-2 OC(O)NHEt 18-1 18-2 OC(O)NHnPr 19-1 19-2 OC(O)NMe₂ mp. 126

[0114] TABLE 2 Compounds of formula (I) wherein R₂₀₁ is cyano; R₂₀₂ isSOCF₃; R₂₁₁ is Cl, X₁ is C—Cl, R₂₁₄ is H and R₂₁₃ is CF₃ or SF₅. Phys.data: melting point (° C.) or NMR (¹H, ¹⁹F-NMR, ppm) Compound CompoundNumber Number (R₂₁₃═CF₃) (R₂₁₃═SF₅) R₂₀₄ Phys. data  1-3  1-4 OH mp. 185 2-3  2-4 OMe mp. 136  3-3  3-4 OEt mp. 157  4-3  4-4 OPr  5-3  5-4O-i-Pr  6-3  6-4 O-n-Bu  7-3  7-4 OCH₂OMe  8-3  8-4 OCH₂CH₂OMe  9-3  9-4OCH₂OEt 10-3 10-4 OCH₂CH₂OEt 11-3 11-4 ONa 19F: −60.9 −72.6 12-3 12-4OC(O)Et 13-3 13-4 OC(O)n-Pr 14-3 14-4 OC(O)H 15-3 15-4 OC(O)NH₂ 16-316-4 OC(O)NHMe 17-3 17-4 OC(O)NHEt 18-3 18-4 OC(O)NHnPr 19-3 19-4OC(O)NMe₂

[0115] TABLE 3 Compounds of formula (I) wherein R₂₀₁ is cyano; R₂₀₂ isSO₂CF₃; R₂₁₁ is Cl, X₁ is C—Cl, R₂₁₄ is H and R₂₁₃ is CF₃ or SF₅. Phys.data: melting point (° C.) or NMR (¹H, ¹⁹F-NMR, ppm) Compound CompoundNumber Number (R₂₁₃═CF₃) (R₂₁₃═SF₅) R₂₀₄ Phys. data  1-5  1-6 OH 19F:−63.8 −79.9 ppm  2-5  2-6 OMe mp. 151  3-5  3-6 OEt mp. 132  4-5  4-6OPr  5-5  5-6 O-i-Pr  6-5  6-6 O-n-Bu  7-5  7-6 OCH₂OMe  8-5  8-6OCH₂CH₂OMe  9-5  9-6 OCH₂OEt 10-5 10-6 OCH₂CH₂OEt 11-5 11-6 OC(O)Me 12-512-6 OC(O)Et 13-5 13-6 OC(O)n-Pr 14-5 14-6 OC(O)H 15-5 15-6 OC(O)NH₂16-5 16-6 OC(O)NHMe 17-5 17-6 OC(O)NHEt 18-5 18-6 OC(O)NHnPr 19-5 19-6OC(O)NMe₂

[0116] TABLE 4 Compounds of formula (I) wherein R₂₀₁ is alkyl orhaloalkyl; R₂₀₂ is SO_(h)R₂₀₃; R₂₁₁ is Cl, X₁ is C—Cl, R₂₁₄ is H andR₂₁₃ is CF₃; Phys. data: melting point (° C.) or NMR (¹H, ¹⁹F-NMR, ppm)Compound No R₂₀₁ R₂₀₂ R₂₀₄ Phys. Data  1-7 CH₃ SCF₃ OH 19F: −45.9 −63.5ppm  2-7 CH₃ SOCF₃ OH  3-7 CH₃ SO₂CF₃ OH  4-7 CH₃ SCClF₂ OH 19F: −30.4−63.7 ppm  5-7 CH₃ SOCClF₂ OH  6-7 CH₃ SO₂CClF₂ OH  7-7 CH₃ SCCl₂F OH 8-7 CH₃ SOCCl₂F OH  9-7 CH₃ SC₂F₅ OH 10-7 CH₃ SC₂H₅ OH 11-7 CH₃ SCF₃OMe 12-7 CH₃ SCF₃ OEt 13-7 CH₃ SMe OH 14-7 C₂H₅ SCF₃ OH 15-7 CF₃ SCF₃ OH16-7 CHF₂ SCF₃ OH 17-7 CF₃ SOCF₃ OH 18-7 CF₃ SO₂CF₃ OH 19-7 CF₃ SCClF₂OH 20-7 CF₃ SCCl₂F OH

[0117] TABLE 5 Compounds of formula (I) wherein R₂₀₂ is SO_(h)R₂₀₃; R₂₁₁is Cl, X₁ is C—Cl, R₂₁₄ is H and R₂₁₃ is CF₃; Phys. data: melting point(° C.) or NMR (¹H, ¹⁹F-NMR, ppm) Compound No R₂₀₁ R₂₀₂ R₂₀₄ Phys. data 1-8 CONH₂ SCF₃ OH mp. 197  2-8 CONH₂ SOCF₃ OH  3-8 CONH₂ SO₂CF₃ OH  4-8CSNH₂ SCF₃ OH mp. 150  5-8 CSNH₂ SOCF₃ OH  6-8 CSNH₂ SO₂CF₃ OH  7-8CONMe₂ SCF₃ OH  8-8 C(NOH)NH₂ SCClF₂ OH mp. 156  9-8 C(NOH)NH₂ SCF₃ OHmp. 184 10-8 COCH₃ SCF₃ OH 19F: −44.5 −61.7 11-8 COCH₃ SCClF₂ OH 19F:−29.4 −61.0 12-8 CONH₂ SCF₃ OEt 13-8 CONH₂ SCClF₂ OEt 14-8Oxadiazolin-3-yl SCF₃ OH 15-8 Oxazolin-2-yl SCF₃ OH 16-8 CON═S(iPr₂)SCF₃ OH 17-8 CON═S(iPr)₂ SOCF₃ OH 18-8 CON═S(iPr)₂ SO2CF₃ OH 19-8 CONH₂SCF₃ OMe mp. 148-151 20-8

[0118] TABLE 6 Compounds of formula (I) wherein R₂₀₁ is CN; R₂₀₂ isSO_(h)R₂₀₃; R₂₁₁ is Cl, X₁ is C—Cl, R₂₁₄ is H and R₂₁₃ is CF₃; Phys.data: melting point (° C.) or NMR (¹H, ¹⁹F-NMR, ppm) Compound No R₂₀₂R₂₀₄ Phys. data  1-9 SCClF₂ OH 19F: −30.7 −63.7  2-9 SOCClF₂ OH  3-9SO₂CClF₂ OH  4-9 SCCl₂F OH  5-9 SOCCl₂F OH  6-9 SO₂CCl₂F OH  7-9 SC₂F₅OH  8-9 SCH₂CF₃ OH  9-9 SCCl₂CF₃ OH 10-9 SCCl₂CH₃ OH 11-9 SC₂H₅ OH 1H:1.25, 3H; 2.71, 3H; 7.72, 2H; 12-9 SCHF₂ OH 13-9 SCClF₂ OEt mp. 91 14-9SOCClF₂ OEt mp. 161 15-9 SCClF₂ OCONMe₂ 16-9 SCClF₂ OCOtBu 17-9 SCH₃ OHmp. 66 18-9 SCH₃ OCONMe₂ 1H: 2.43, 3H; 2.96, 6H; 7.75, 2H; 19-9 SCBrF₂OH 20-9 SCCl₃ OH 21-9 SCCl₂F OMe mp. 154 22-9 SOCCl₂F OMe mp. 136 23-9SO₂CCl₂F OMe mp. 189 24-9 SO₂CClF₂ OEt mp. 130 25-9 SCClF₂ OMe mp. 8726-9 SOCClF² OMe mp. 139 27-9 SO²CClF² OMe mp. 166

[0119] TABLE 7 Compounds of formula (I) wherein R₂₀₁ is CN; R₂₀₂ isSO_(h)R₂₀₃; R₂₁₁ is Cl, X₁ is C—Cl, R₂₁₄ is H and R₂₁₃ is CF₃; Phys.data: melting point (° C.) or NMR (¹H, ¹⁹F-NMR, ppm) Compound No R₂₀₂R₂₀₄ Phys. data  1-10 SCF₃ OCH₂—CCH 19F: −44.6 −63.8  2-10 SCF₃OCH₂COOEt mp. 71  3-10 SCF₃ OCOtBu mp. 82  4-10 SCF₃ OCO-Ph-4-OMe 19F:−43.5 −63.9  5-10 SCF₃ OSO₂Me mp. 110  6-10 SCF₃ OCO-Pyrrolidin mp. 101 7-10 SCF₃ OCO-Morpholin 19F: −43.5 −63.8  8-10 SCF₃ OCO—N(i-Pr)₂ mp.120  9-10 SCF₃ OCO—NPh₂ mp. 142 10-10 SCF₃ OCO—N(Me)Ph 19F: −43.6 −63.711-10 SCF₃ OCO-Carbazol mp. 148 12-10 SCF₃ OCO-Adamantyl mp. 142 13-10SCF3 OCO-Mesityl mp. 103 14-10 SCF3 OCH₂Ph mp. 73 15-10 SCF3OSO₂-4-Tolyl 16-10 SCF3 O—C(NMe)Nme₂ 17-10 SCF3 O—CH═NC₂H₄OEt 18-10 SCF3OCH₂CONH₂ mp. 156 19-10 SCF3 O—C(N(i-Pr))NHiPr 20-10 SCF3 O—C(S)—NHEt

[0120] TABLE 8 Compounds of formula (I) wherein R₂₁₁ is Cl, X₁ is C—Cl,R₂₁₄ is H and R₂₁₃ is CF₃; Phys. data: melting point (° C.) or NMR (¹H,¹⁹F-NMR, ppm) Compound No R₂₀₁ R₂₀₂ R₂₀₄ Phys. data  1-11 CN4,5-Dicyano- OH imidazol-2-yl  2-11 CN 4,5-Dicyano- OEt imidazol-2-yl 3-11 CH₃ 4,5-Dicyano- OH imidazol-2-yl  4-11 CH₃ 4,5-Dicyano- OEt 1H:1.28, 3H; 2.55, imidazol-2-yl 3H; 4.08, 2H; 7.77, 2H;  5-11 CN —CH═CCl₂OEt  6-11 CN —CH₂CH═CH₂ OAllyl mp. 62-66  7-11 CN —CH═CBr₂ OEt  8-11 CNCyclopropyl OEt  9-11 CN c-C₆H₁₁ OEt 10-11 CN NO₂ OH mp. 107 11-11 CNNO₂ OEt 12-11 CN —CC—Me OEt 13-11 CN —CC—SiMe₃ OEt

[0121] TABLE 9 Compounds of formula (I) wherein R₂₀₁ is CN; R₂₀₂ isSO_(h)R₂₀₃; R₂₁₁ is Cl, R₂₁₄ and R₂₁₃ form the unit CF₂OCF₂; Phys. data:melting point (° C.) or NMR (¹H, ¹⁹F-NMR, ppm) Compound No R₂₀₂ R₂₀₄X═CR₂₁₂ Phys. data  1-12 SCF₃ OH CH  2-12 SCF₃ OH C—Cl  3-12 SCF₃ OEtC—Cl  4-12 SOCF₃ OH CH  5-12 SOCF₃ OH C—Cl  6-12 SO₂CF₃ OH CH  7-12SO₂CF₃ OH C—Cl  8-12 SCClF₂ OH C—Cl  9-12 SCCl₂F OH C—Cl 10-12 SC₂H₅ OHC—Cl

[0122] TABLE 10 Compounds of formula (I) wherein R₂₀₁ is CN; R₂₀₂ isSO_(h)R₂₀₃; R₂₁₁ is Cl, X₁ is C—Cl, R₂₁₄ is H and R₂₁₃ is OCF₃; Phys.data: melting point (° C.) or NMR (¹H, ¹⁹F-NMR, ppm) Compound No R₂₀₂R₂₀₄ Phys data  1-13 SCF₃ OH  2-13 SOCF₃ OH  3-13 SO₂CF₃ OH  4-13 SCF₃OMe mp. 101  5-13 SOCF₃ OMe mp. 104  6-13 SO₂CF₃ OMe mp. 117  7-13SCCl₂F OMe mp. 123  8-13 SCF₃ OEt  9-13 SOCF₃ OEt 10-13 SO₂CF₃ OEt

[0123] Methods of Synthesis

[0124] Method 1

[0125] The compounds of formula (I) and (II) with R₂₀₄/R₂₄═OH andR₂₂═SR₂₃ can be synthesized by reacting 5-hydroxypyrazoles withsulfenylchlorides with or without bases in organic solvents (see e.g.EP-A-295 117):

[0126] Method 2

[0127] The compounds of formula (I) and (II) with R₂₀₄/R₂₄═OH andR₂₂=SR₂₃ can be synthesized by reacting 5-hydroxypyrazoles withdisulfurdichloride. The resulting pyrazoledisulfides can be alkylated toyield 4-pyrazolsulfides (see e.g. EP-A-374 061, EP295117, C. Wakselman,J. Chem. Soc. Perkin Trans 1, 1992 3371-3375):

[0128] Method 3

[0129] The compounds of formula (I) and (II) with R₂₀₄/R₂₄═OH andR22═S(O)aR₂₃ (a=1,2) can be synthesized by reacting pyrazolsulfidesR22═SR₂₃ with oxidizing agents like peroxy compounds (hydrogenperoxide,organic peroxides as peroxyaceticacid), halogenderivatives (likeperiodate salts) and others to obtain sulfoxides R₂₂═SOR₂₃ and sulfonesR₂₂═SO₂R₂₃ (see e.g. EP-A-295 117).

[0130] In another aspect of the present invention, compounds of formula(II) wherein R₂₄ is HC(O)O—, R₂₅C(O)O—, R₂₅OC(O)O—, or R₂₅S(O)_(n)C(O)Oand R₂₁, R₂₂, R₃₁, R₃₃, X and n are defined above are generally preparedby reaction of compounds of formula (II) wherein R₂₄ is OH and R₂₁, R₂₂,R₃₁, R₃₃, X and n are defined above with a compounds of formulae (III),(IV), (V), and (VI) respectively wherein X₂ is a leaving group such as ahalogen atom or an acetyl group: HC(O)X₂ R₂₅C(O)X₂ R₂₅OC(O)X₂R₂₅S(O)_(n)C(O)X₂ (III) (IV) (V) (VI)

[0131] Compounds of general formula (II) wherein of formula (II) whereinR₂₄ is OH and R₂₁, R₂₂, R₃₁, R₃₃, X and n are defined above may beprepared by methods known in the art generally or by methods describedin International Patent Publications WO 94/21606, WO 97/07102, WO98/24767, WO 98/28277, WO 98/28278 and WO 98/28279, European PatentApplication 385809, and U.S. Pat. Nos. 5,232,940, 5,047,550 or othermethods known to the person skilled in the art.

[0132] The present invention also relates to a composition comprising aparasiticidally effective, substantially non-emetic amount of a compoundof formula (I) or a salt thereof and an acceptable carrier. Acceptablecarriers for the use of the compounds are generally known to the skilledaddressee concerned with pest control in animals, particularly domesticanimals, most preferably dogs or cats.

[0133] The compositions which can be used in the invention can comprisegenerally from about 0.001 to 95% of the compound of formula (I) or asalt thereof. The remainder of the composition up to 100% comprises acarrier as well as generally various additives. In this specificationand the accompanying claims, percentages are by weight.

[0134] The diluted liquid formulations generally comprise from about0.001 to about 3% of compound of formula (1) or a salt thereof,preferably from about 0.1 to about 0.5%. Solid formulations generallycomprise from about 0.1 to about 8% of compound of formula (I) or a saltthereof, preferably from about 0.5 to about 1.5%.

[0135] Compositions for oral administration comprise one or more of thecompounds of general formula (I) or salts thereof in association withveterinarily acceptable carriers or coatings and include, for example,tablets, pills, capsules, gels, drenches, medicated feeds, medicateddrinking water, medicated dietary supplements, slow-release boluses orother slow-release devices intended to be retained within thegastro-intestinal tract. Any of these may incorporate the activeingredients contained within micro-capsules or coated with acid-labileor alkali-labile or other pharmaceutically acceptable enteric coatings.Feed premixes or concentrates containing compounds of the presentinvention for use in preparation of medicated diets, drinking water orother materials for consumption by animals may also be used. In a highlypreferred embodiment, the compositions are administered postprandially,preferably from just after a meal to 2 hours after the meal.

[0136] In a highly preferred embodiment, there is provided a productwhich is readily chewed by the animal and which product does generallynot allow human contamination when the product is provided to the animalby hand.

[0137] The compounds of general formula (I) or salts thereof may beadministered before, during or after meals. The compounds of generalformula (i) or salts thereof may be mixed with a carrier and/or afoodstuff.

[0138] According to the present invention the compound of formula (I) ora salt thereof is administered orally in a dose to the animal in a doserange generally from 0.1 to 500 mg/kg of the compound of formula (I) ora salt thereof per kilogram of animal body weight (mg/kg), preferablyfrom 1 to 100 mg/kg, more preferably from 1 to 50 mg/kg, even morepreferably from 2 to 25 mg/kg, most preferably from 3 to 15 mg/kgAccording to the present invention, the frequency of treatment of theanimal, preferably the domestic animal to be treated by the compound offormula (I) or a salt thereof is generally from about once per week toabout once per year, preferably from about once every two weeks to aboutonce every six months, more preferably from about once every two weeksto once every three months, and most preferably from about once everytwo weeks to about once every six weeks.

[0139] Generally the animal to be treated is a domestic animal,preferably a domestic companion animal. More preferably the animal to betreated is a dog and/or a cat.

[0140] Accordingly, in a preferred embodiment there is provided a methodof controlling parasites in or on a cat comprising administering orallyto the cat a parasitically effective, substantially non emetic amount ofa 1-arylpyrazole of formula (I).

[0141] In a further preferred embodiment there is provided a method ofcontrolling parasites in or on a dog comprising administering orally tothe dog a parasitically effective, substantially non emetic amount of a1-arylpyrazole of formula (I).

[0142] The present invention also relates to a composition comprising aparasiticidally effective amount of a compound of formula (II) or a saltthereof and an acceptable carrier. Acceptable carriers for the use ofthe compounds are generally known to the skilled addressee concernedwith pest control in animals, particularly domestic animals, mostpreferably dogs or cats.

[0143] In another aspect of the present invention, the compounds offormula (II) or salts thereof may be used in the field of veterinarymedicine or livestock husbandry or in the maintenance of public healthagainst arthropods, helminths or protozoa which are parasitic internallyor externally upon vertebrates, particularly warm-blooded vertebrates,for example domestic animals, e.g. cattle, sheep, goats, equines, swine,poultry, dogs or cats.

[0144] The compounds to animals infested by or exposed to infestation byarthropods, helminths or protozoa, by parenteral, oral or topicalapplication of compositions in which the active ingredient exhibits animmediate and/or prolonged action over a period of time against thearthropods, helminths or protozoa, for example by incorporation in feedor suitable orally-ingestible pharmaceutical formulations, edible baits,salt licks, dietary supplements, pour-on formulations, sprays, baths,dips, showers, jets, dusts, greases, shampoos, creams, wax smears orlivestock self-treatment systems.

[0145] Solid or liquid compositions for application topically toanimals, timber, stored products or household goods usually contain fromabout 0.00005% to about 90%, more particularly from about 0.001% toabout 10%, by weight of one or more compounds of formula (II) orveterinarily acceptable salts thereof. For administration to animalsorally or parenterally, including percutaneously solid or liquidcompositions, these normally contain from about 0.1% to about 90% byweight of one or more compounds of formula (II) or veterinarilyacceptable salts thereof.

[0146] Medicated feedstuffs normally contain from about 0.001% to about3% by weight of one or more compounds of formula (II) or veterinarilyacceptable salts thereof.

[0147] Concentrates or supplements for mixing with feedstuffs normallycontain from about 5% to about 90%, preferably from about 5% to about50%, by weight of one or more compounds of formula (II) or veterinarilyacceptable salts thereof. Mineral salt licks normally contain from about0.1% to about 10% by weight of one or more compounds of formula (II) orveterinarily acceptable salts thereof.

[0148] Dusts or liquid compositions for application to livestock, goods,premises or outdoor areas may contain from about 0.0001% to about 15%,more especially from about 0.005% to about 2.0%, by weight, of one ormore compounds of formula (II) or veterinarily acceptable salts thereof.Suitable concentrations in treated waters are between about 0.0001 ppmand about 20 ppm, more particularly about 0.001 ppm to about 5.0 ppm. ofone or more compounds of formula (II), or veterinarily acceptable saltsthereof, and may be used therapeutically in fish farming withappropriate exposure times. Edible baits may contain from about 0.01% toabout 5%, preferably from about 0.01% to about 1.0%, by weight, of oneor more compounds of formula (II) or veterinarily acceptable saltsthereof.

[0149] When administered to vertebrates parenterally, orally or bypercutaneous or other means, the dosage of compounds of formula (II), orveterinarily acceptable salts thereof, will depend upon the species,age, or health of the vertebrate and upon the nature and degree of itsactual or potential infestation by arthropod, helminth or protozoanpests. A single dose of about 0.1 to about 500, preferably from 0.1 toabout 100 mg, preferably about 2.0 to about 20.0 mg, per kg body weightof the animal or doses of about 0.01 to about 20.0 mg, preferably about0.1 to about 5.0 mg, per kg body weight of the animal per day, forsustained medication, are generally suitable by oral or parenteraladministration. By use of sustained release formulations or devices, thedaily doses required over a period of months may be combined andadministered to animals on a single occasion.

[0150] The compounds of the invention may be administered mostadvantageously with another parasiticidally effective material, such asan endoparasiticide, and/or an ectoparasiticide, and/or anendectoparasiticide. For example, such compounds include macrocycliclactones such as avermectins or milbemycins e.g., ivermectin; pyratel(generally adminsitered as pyrantel pamoate) or an insect growthregulator such as lufenuron or methoprene.

[0151] By the term “parasites” as used in the specification and claimsis meant endoparasites and ectoparasites of warm-blooded animals,particularly ectoparasites. Preferably, fleas and/or ticks arecontrolled by the method of the present invention.

[0152] Illustrative of specific parasites of various host animals whichmay be controlled by the methods of this invention include arthropodssuch as:

[0153] Mites: Mesostigmata spp. e.g. mesostigmatids such as the chickenmite,

[0154]Dermanyssus gallinae; itch or scab mites such as Sarcoptidae spp.for example

[0155]Sarcoptes scabiei; mange mites such as Psoroptidae spp. includingChorioptes bovis and Psoroptes ovis; chiggers e.g. Trombiculidae spp.for example the north american chigger, Trombicula alfreddugesi;

[0156] Ticks: e.g., soft-bodied ticks including Argasidae spp. forexample Argas spp. and Ornithodoros spp; hard-bodied ticks includinglxodidae spp., for example Rhipicephalus sanguineus, and Boophilus spp.;

[0157] Lice: sucking lice, e.g., Menopon spp. and Bovicola spp.; bitinglice, e.g., Haematopinus spp., Linognathus spp. and Solenopotes spp.;

[0158] Fleas: e.g., Ctenocephalides spp., such as dog flea(Ctenocephalides canis) and cat flea (Ctenocephalides felis); Xenopsyllaspp. such as oriental rat flea [Xenopsylla cheopis]; and Pulex spp. suchas human flea [Pulex irritans];

[0159] True bugs: e.g., Cimicidae or including the common bed bug (Cimexlectularius); Triatominae spp. including triatomid bugs also known askissing bugs; for example Rhodnius prolixus and Triatoma spp.;

[0160] bloodsucking adult flies: (e.g., horn fly [Haematobia irritans],horse fly [Tabanus spp.], stable fly [Stomoxys calcitrans], black fly[Simulium spp.], deer fly [Chrysops spp.], louse fly [Melophagusovinus], tsetse fly [Glossina spp.], mosquitoes [Culex spp., Anophelesspp., and Aedes spp.); and

[0161] parasitic fly maggots: (e.g., bot fly [Oestrus ovis and Cuterebraspp.], blow fly [Phaenicia spp.], screwworm [Cochliomyia hominivorax],cattle grub [Hypoderma spp.], fleeceworm.

[0162] The present invention also provides for the use of a compound offormula (I) or a salt thereof hereinbefore described as a therapeuticagent, preferably for animals, more preferably for domestic animals.

[0163] The veterinary composition may be sterile or non-sterile. It maybe a liquid (e.g. aqueous) or solid (e.g., dry) composition, inparticular a freeze-dried composition, which, by addition of water oranother liquid, orally effective solutions may be prepared.

[0164] The present invention also provides for the use of a compound offormula (I) or a salt thereof as hereinbefore defined for themanufacture of a veterinary composition for the control of parasites inor on an animal.

[0165] In a further embodiment of the invention there is provided theuse of a compound of formula (I) or salt thereof for controllingparasites in or on an animal without causing emesis of the animal.

[0166] Preferred is the use for orally administering the compound to theanimal, which is preferably a domestic animal, highly preferred a cat ora dog.

[0167] In a further embodiment of the invention there is provided theuse of a compound of formula (I) or salt thereof for the manufacture ofa substantially non emetic composition, for controlling parasites in oron an animal, preferably for oral administering.

[0168] The present invention also relates to a method of cleaninganimals in good health comprising the application to the animal of acompound of formula (I) or a salt thereof as hereinbefore defined to theanimal.

[0169] The method of cleaning an animal is not a method of treatment bytherapy of the animal body per se, because

[0170] (a) the animal is in good health and requires no substantialtreatment to correct a deficiency of health;

[0171] (b) the cleaning of the animal is not intended to be done byveterinary personnel, but by persons interested in the cleaning of theanimal; and

[0172] (c) the purpose of such cleaning is to avoid unpleasantconditions for humans and the environment in which humans inhabit so asto not infest the said humans with arthropods carried by the animal.

[0173] By “carrier” is meant an organic or inorganic material, which canbe natural or synthetic, and which is associated with the compound andwhich facilitates its application to the animal. This carrier is thusgenerally inert and should be arthropocidally acceptable. The carriercan be solid (e.g., clay, silicates, silica, resins, wax.) or liquid(e.g., water, alcohols, ketones, oil solvents, polar aprotic solvents)An example of an oil solvent is corn oil. An example of a polar aproticsolvent is dimethyl sulfoxide.

[0174] The compounds of the invention also have utility in the controlof arthropod or nematode pests of plants. The active compound isgenerally applied to the locus in which arthropod or nematodeinfestation is to be controlled at a rate of about 0.005 kg to about 25kg of active compound per hectare of locus treated, preferably 0.02 to 2kg/ha. Under ideal conditions, depending on the pest to be controlled,the lower rate may offer adequate protection. On the other hand, adverseweather conditions, resistance of the pest and other factors may requirethat the active ingredient be used in higher proportions. For foliarapplication, a rate of 0.01 to 1 kg/ha may be used.

[0175] When the pest is soil-borne, the formulation containing theactive compound is distributed evenly over the area to be treated in anyconvenient manner. Application may be made, if desired, to the field orcrop-growing area generally or in close proximity to the seed or plantto be protected from attack. The active component can be washed into thesoil by spraying with water over the area or can be left to the naturalaction of rainfall. During or after application, the formulation can, ifdesired, be distributed mechanically in the soil, for example byploughing or disking.

[0176] Application can be prior to planting, at planting, after plantingbut before sprouting has taken place or after sprouting.

[0177] The compounds of the invention may be applied in solid or liquidcompositions to the soil principally to control those nematodes dwellingtherein but also to the foliage principally to control those nematodesattacking the aerial parts of the plants (e.g. aphelenchoides spp. andditylenchus spp. listed above).

[0178] The compounds of the invention are of value in controlling pestswhich feed on parts of the plant remote from the point of application,e.g. leaf feeding insects are killed by the subject compounds applied toroots. In addition the compounds may reduce attacks on the plant bymeans of antifeeding or repellent effects.

[0179] The compounds of the invention are of particular value in theprotection of field, forage, plantation, glasshouse, orchard andvineyard crops, or ornamentals and of plantation and forest trees, forexample, cereals (such as maize, wheat, rice, sorghum), cotton, tobacco,vegetables and salads (such as beans, cole crops, curcurbits, lettuce,onions, tomatoes and peppers), field crops (such as potato, sugar beet,ground nuts, soyabean, oil seed rape), sugar cane, grassland and forage(such as maize, sorghum, lucerne), plantations (such as of tea, coffee,cocoa, banana, oil palm, coconut, rubber, spices), orchards and groves(such as of stone and pip fruit, citrus, kiwifruit, avocado, mango,olives, and walnuts), vineyards, ornamental plants, flowers and shrubsunder glass and in gardens and parks, forest trees (both deciduous andevergreen) in forests, plantations and nurseries.

[0180] They are also valuable in the protection of timber (standing,felled, converted, stored or structural) from attack by sawflies (e.g.urocerus) or beetles (e.g. scolytids, platypodids, lyctids, bostrychids,cerambycids, anobiids), or termites, for example, reticulitermes spp.,heterotermes spp., coptotermes.

[0181] They have applications in the protection of stored products suchas grains, fruits, nuts, spices and tobacco, whether whole, milled orcompounded into products, from moth, beetle and mite attack. Alsoprotected are stored animal products such as skins, hair, wool andfeathers in natural or converted form (e.g. as carpets or textiles) frommoth and beetle attack; also stored meat and fish from beetle, mite andfly attack.

[0182] The disclosure in U.S. provisional application No. 60/168,658from which this application claims priority is incorporated herein byreference.

[0183] This invention is further illustrated by the following examples,without limiting it thereto.

EXAMPLES AND PREPARATIONS Example 1

[0184] Preparation of1-(2,6-Dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfinyl-5-hydroxypyrazole.To a solution of 15 g (35.5 mmol) of1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfenyl-5-hydroxypyrazolein 125 ml of dichloromethane at room temperature was added a solution ofm-chloroperbenzoic acid (8.76 g, 70%, 35.5 mmol) in 375 ml ofdichloromehane. The resulting solution was stirred at room temperaturefor 17 hr. It was then concentrated and triturated with ethyl acetateand heptane(1:2). Upon filtration a solid was obtained. This solid wasdissolved in ethyl acetate and stirred with saturated sodium bicarbonatesolution. Ther layers were separated and the aqueous layer was extractedwith three times of ethyl acetate. The combined orcianic layer was dried(magnesium sulfate) and concentrated. Upon chromatographic purificationvia silica gel column, a solid (5.7 g, 13.01 mol, 37%) was obtained asthe desired product, mp 185-187d.

Example 2

[0185] Preparation of1-(2,6-Dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfonyl-5-hydroxypyrazole.To the solution of 2 g (4.74 mmol) of1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfenyl-5-hydroxypyrazolein 1,2-dichloroethane was added 1.83 ml (9.52 mmol, 35% in acetic acid)of peracetic acid at room temperature. The resulting solution was heatedup to 60 C. for 9 hr. It was then cooled and concentrated to give 2.05 gof residue. Upon chromatographic purification via silica gel columneluting with gradient solvent mixture (heptance/ethyl acetate), an oil(1.08 g, 2.38 mmol, 50.2% yield) was obtained as the desired productwith 98% HPLC puriety; F-NMR, −60.999 ppm (AR-CF3), −79.893 ppm(SO2CF3). H-NMR, 8.18 ppm (s, 2H).

Example 3

[0186] Preparation of1-(2,6-dichloro-4-trifluoromethylphenyl)-3-amido-4-trifluoromethylsulfenyl-5-hydroxypyrazole.To the mixture of1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfenyl-5-hydroxypyrazole(3.0 g, 7.13 mmol) and concentrated sulfuric acid (3 ml) was heated at100 C. for 3 hr. The reaction mixture was cooled and poured intoice-water. A solid was collected via filtration and was washed withwater. It was then vacuum dried to obtain a solid (2.88 g, 6.56 mmol,92% yield) with 98% HPLC puriety, m. p. 197-198 C.

Example 4

[0187] Preparation of1-(2,6-dichloro-4-trifluoromethylphenyl)-3-thioamido-4-trifluoromethylsulfenyl-5-hydroxypyrazole.To the mixture of1-(2,6-dichloro-4-trifluoromethylphenyl)-3-amido-4-trifluoromethylsulfenyl-5-hydroxypyrazole(1 g, 2.28 mmol) and Lawesson's reagent (0.49 g, 1.21 mmol) in toluenewas heated up to reflux for 4 hr. The reaction mixture turned into asolution during this time. This solution was then cooled , concentrated,and via chromatographic purification to provide a solid (0.283 g, 0.623mmol, 27.3% yield) with 96% HPLC puriety m. p. 150-151 decomp.

Example 5

[0188] Preparation of1-(2,6-Dichloro-4-trifluoromethylphenyl)-3-oximicamido-4-trifluoromethylsulfenyl-5-hydroxypyrazole.To the solution of1-(2,6-dichloro-4-trifliuoromethylphenyl)-3-cyano-4-trifluoromethylsulfenyl-5-hydroxypyrazole(3.0 g, 7.11 mmol) in 15 ml of methanol at room temperature was addedhydroxyamine hydrochloride (0.59 g, 8.53 mmol) and triethylamine (0.94g, 9.24 mmol). The resulting mixture was stirred at room temperature fora total of 48 hr with additional hydroxyamine hydrochloride (1.18 g,17.06 mmol) and triethylamine (1.88 g, 18.5 mmol) added portionwise. Theresulting reaction mixture was concentrated and then dissolved in ethylacetate. The organic layer was washed with saturated ammonium chloride,water, dried (sodium sulfate), concentrated to give a brown oil whichsolidified after standing, m. p. 184 C.

Example 6

[0189] Preparation of1-(2,6-Dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfenyl-5-trimethylacetoxypyrazole.To the solution of1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfenyl-5-hydroxypyrazole(7.00 g, 16.6 mmol) and pyridine (4.91 g, 62.1 mmol) in1,2-dichloroethane at room temperature was added trimethylacetylchloride (4.37 g, 36.2 mmol) dropwise. Ice bath was used to maintain thetemperature of the reaction. After 20 hr at room temperature, theorgainc layer was washed with five times of aqueous KHS04 till theaqueous solution was at pH 1. The orgainc layer was then dried (Mg SO4)and concentrated to give a solid residue. Upon chromatographicpurification via silica gel column of the solid residue, aftertrituration with pentane, a off white solid (2.403 g, 28.6% yield, 97.0%HPLC puriety) was provided as the desired product, m. p. 82-83 C.

Example 7

[0190] Preparation of1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-chlorodifluoromethylsulfenyl-5-hydroxypyrazole.To the solution of1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-5-hydroxypyrazole (12.0g, 37.3 mmol.) and pyridine (3.25 g, 41.0 mmol) in dichloromethane at−50-−60 C. was added chlorodifluoromethanesulfenyl chloride (8.1 g, 46.6mmol). The resulting solution was gradually warmed up to roomtemperature. After 20 hr, the organic layer was washed five times withwater. It was then washed with brine and dried (Na2SO4) to provide anoil. Upon chromatographic purification of the oil , a total of 11.6 g(26.4 mmol., 71% yield) of the desired product with 97% HPLC puriety wasisolated. F-NMR: −30.05 ppm (CCIF2), −63.80 ppm (ArCF3).

Biological Example

[0191] The compounds1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluromethylthio-5-hydroxypyrazole,1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluromethylsulfinyl-5-hydroxypyrazoleand1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluromethylsulfonyl-5-hydroxypyrazoleare formulated as a 30 mg/mL formulations in a 1:1 volume/volumesolution of dimethyl sulfoxide and corn oil. Using this formulation,mixed breed dogs and cats are treated at a rate of 10 mg of the compoundper kg (mg/kg)of body weight of the dog and 20 mg/kg of the cat treated.The animals are fasted for at least 8 hours prior to treatment, fed halfof the daily ration immediately prior to treatment, then allowed accessto the remainder of the daily ration immediately following treatment.

[0192] All dogs are infested with cat fleas (Ctenocephalides felis) andwith ticks (Rhipicephalus sanguineus) 1 day prior to administration ofthe compound. Cats are only infested with fleas. The initial flea andtick counts are performed 1 day after the administration of thecompounds. At 7, 14, 21 and 28 days after treatment the dogs arere-infested with ticks and 8, 15, 22 and 29 days after treatment thedogs and cats are re-infested with fleas. At 1, 9, 16, 23 and 30 daysafter treatment the control of fleas and ticks in treated dogs and catsis determined versus a group of infested dogs and cats which receive aplacebo consisting of a 1:1 volume/volume solution of dimethyl sulfoxideand corn oil. To determine the efficacies of the compounds, thearthropods are combed from the animals and counted.

[0193] Satisfactory results are obtained for many of the above-mentionedcompounds in any of the three areas of evaluation without anysignificant side effect for a period ranging from eight to thirty days:control of flea on dog, control of tick on dog, and control of flea oncat. They are:1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfenyl-5-trimethylacetoxypyrazole3-10,1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfenyl-5-ethoxypyrazole3-1,1-(2,6-dichloro4-trifluoromethylphenyl)-3-cyano-4-chlorodifluoromethylsulfenyl-5-hydroxypyrazole1-9,1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfenyl-5-hydroxypyrazole1-1,1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfonyl-5-hydroxypyrazole1-5,1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfinyl-5-hydroxypyrazole1-3,1-(2,6-dichloro-4-trifluormethyl(phenyl)-3-cyano-4-trifluormethylsulfonyl-5-N,N-dimethylcarbamyloxypyrazole19-1.

1. A method of controlling parasites in or on an animal comprisingadministering to the animal a parasiticidally effective, substantiallynon-emetic amount of a 1-arylpyrazole of formula (I):

wherein: R₂₀₁ is cyano, C(O)alkyl, C(S)NH₂, C(NH)OR₂₀₃, C(NH)SR₂₀₃,alkyl, C(═NOH)NH₂, C(═NNH₂)NH₂, C(O)NH₂, C(O)NHR₂₀₅, C(O)NR₂₀₅R₂₀₆,haloalkyl or heterocyclyl from the group:

optionally substituted by R₂₀₃; R₂₀₂ is S(O)_(h)R₂₀₃, C₂-C₆ alkenyl,C₂-C₆ haloalkenyl, cycloalkyl, halocycloalkyl, cycloalkyl-alkyl , C₂-C₆alkynyl, nitro or imidazol-2-yl optionally substituted by alkyl, alkoxy,haloalkyl, halogen, cyano and/or nitro; R₂₀₃ is alkyl or haloalkyl; R₂₀₄is —OH, R₂₀₅O—, HC(O)O—, R₂₀₅C(O)O—, R₂₀₅OC(O)O—, NH₂C(O)O—,R₂₀₅NHC(O)O—, R₂₀₅R₂₀₆NC(O)O—, R₂₀₅S(O)_(n)C(O)O—, R₂₀₆SO₂O—,aryl-SO₂O—, (C₄-C₇)-oxacycloalkyloxy, R₂₀₅R₂₀₆N—C(N R₂₀₅)—O—,R₂₀₅R₂₀₆N—C(NH)—O—, R₂₀₅N H—C(NR₂₀₅)—O—, R₂₀₅NH—C(NH)—O—, R₂₀₅N═CH—O—,R₂₀₅N═C(R₂₀₆)—O—, R₂₀₅NH—C(S)—O—, R205R₂₀₆N—C(S)—O—; R₂₀₅ is alkyl,haloalkyl, cycloalkyl, halocycloalkyl, alkoxyalkyl, haloalkoxyalkyl,adamantyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,haloalkylaminoalkyl, di(haloalkyl)aminoalkyl, aryl optionallysubstituted, hetaryl optionally substituted, arylalkyl optionallysubstituted, hetarylalkyl optionally substituted, C₂-C₆ alkenyl, C₂-C₆alkinyl; R₂₀₆ is alkyl, haloalkyl, cycloalkyl, halocycloalkyl,alkoxyalkyl, haloalkoxyalkyl, aryl optionally substituted, hetaryloptionally substituted, arylalkyl optionally substituted, hetarylalkyloptionally substituted; or R₂₀₅ and R₂₀₆ may form together with thenitrogen to which they are attached a 3 to 7 membered ring whichadditionally may contain one or more heteroatoms selected from nitrogen,oxygen and sulfur; X₁ is selected from nitrogen and C-R₂₁₂; R₂₁₁, R₂₁₂are independently selected from halogen, hydrogen, CN, C₁-C₃ alkyl andNO₂; R₂₁₃ is selected from halogen, haloalkyl, haloalkoxy, —S(O)_(k)CF₃,and —SF₅ or forms a ring with R₂₁₄; R₂₁₄ is hydrogen or may constitutetogether with R₂₁₃ a group of OCF₂O, CF₂OCF₂, CF₂OCF₂O and CF₂CF₂O,which forms together with the carbons they are attached to a five to sixmembered ring; and h, k and n are independently selected from 0, 1, and2; and veterinarily acceptable salts thereof.
 2. A method of controllingparasites in or on an animal as claimed in claim 1 by administering tothe animal an 1-arylpyrazole of formula (II):

wherein: R₂₁ is cyano, C(═S)NH₂, C(═NOH)NH₂ or C(═NNH₂)NH₂; R₂₂ isS(O)_(m)R₂₃; R₂₃ is alkyl or haloalkyl; R₂₄ is OH, HC(O)O—, R₂₅C(O)O—,R₂₅OC(O)O— or R₂5S(O)_(n)C(O)O— R₂₅ is alkyl, haloalkyl, cycloalkyl,halocycloalkyl, alkoxyalkyl, haloalkoxyalkyl, adamantyl, adamantyl,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, haloalkylaminoalkyl,di(haloalkyl)aminoalkyl, aryl optionally substituted, hetaryl optionallysubstituted, arylalkyl optionally substituted, hetarylalkyl optionallysubstituted, C₂-C₆ alkenyl, C₂-C₆ alkinyl, or two groups R₂₅ may formtogether with the nitrogen to which they are attached a 3 to 7 memberedring which additionally may contain one or more heteroatoms selectedfrom nitrogen, oxygen and sulfur; X is selected from nitrogen and C—R₃₂;R₃₁ and R₃₂ are independently selected from halogen, hydrogen, CN, C₁-C₃alkyl and NO₂; R₃₃ is selected from halogen, haloalkyl, haloalkoxy,—S(O)_(r)CF₃, and —SF₅ or forms a ring together with R₃₄; R₃₄ ishydrogen or may constitute together with R₂₁₃ a group of OCF₂O, CF₂OCF₂,CF₂OCF₂O and CF₂CF₂O, which forms together with the carbons they areattached to a five to six membered ring; m is 0, 1 or 2; r is selectedfrom 0, 1, and 2; and veterinarily acceptable salts thereof; providedthat if R₂₁ is cyano then R₂₄ is not R₂₅R₂₅—N—C(O)—O—.
 3. A compound offormula (II) or salt there of as hereinbefore described in claim 2 withthe proviso that the compound is not1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthio-5-hydroxypyrazole.4. A compound according to claim 3 wherein R₂₁ is cyano; R₂₂ isS(O)_(m)R₂₃; R₂₃ is haloalkyl, preferably CF₃; R₂₄ is OH; X is selectedfrom nitrogen and C—R₃₂; R₃₁ and R₃₂ are independently selected fromhalogen, R₃₃ is selected from halogen, haloalkyl, haloalkoxy,—S(O)_(r)CF₃, and —SF₅; m and r are independently selected from 0, 1,and
 2. 5. The compound of formula (I) as defined in claim 1 or thecompound of formula (II) as defined in any one of claims 2, 3 or 4 whichis1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluromethylsulfinyl-5-hydroxypyrazole.6. The compound of formula (I) as defined in claim 1 or the compound offormula (II) as defined in any one of claims 2, 3 or 4 which is1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluromethylsulfonyl-5-hydroxypyrazole.7. A composition comprising a parasiticidally effective, amount of acompound of formula (I) or (II) or a salt thereof as defined in any oneof the foregoing claims and an acceptable carrier.
 8. A compositioncomprising a parasiticidally effective, amount of a compound of formula(II) or a salt thereof and an acceptable carrier as defined in any oneof claims 2, 3, 4, 5 or
 6. 9. The method according to claims 1 whereinthe animal is a domestic animal.
 10. The method according to claim 1wherein the 1-arylpyrazole is administered orally in a dose to theanimal in a dose range from 0.1 to 500 mg/kg.
 11. A compound of formula(I) according to claim 1 wherein R₂₀₁ is cyano, C(O)alkyl, C(S)NH₂,C(NH)OR₂₀₃, C(NH)SR₂₀₃, alkyl, C(═NOH)NH₂, C(═NNH₂)NH₂, C(O)NH₂,C(O)NHR₂₀₅; C(O)NR₂₀₅R₂₀₆, haloalkyl or heterocyclyl from the group:

optionally substituted by R₂₀₃; and/or R₂₀₂ is S(O)_(h)R₂₀₃, C₂-C₆alkenyl, C₂-C₆ haloalkenyl, cycloalkyl, halocycloalkyl, cycloalkyl-alkyl, C₂-C₆ alkynyl, nitro or imidazol-2-yl optionally substituted by alkyl,alkoxy, haloalkyl, halogen, cyano and/or nitro; and/or R₂₀₄ is —OH,R₂₀₅O—, HC(O)O—, R₂₀₅C(O)O—, R₂₀₅OC(O)O—, NH₂C(O)O—, R₂₀₅NHC(O)O—,R₂₀₅R₂₀₆NC(O)O—, R₂₀₅S(O)_(n)C(O)O—, R₂₀₆SO₂O—, aryl-SO₂O—,(C₄-C₇)-oxacycloalkyloxy, R₂₀₅R₂₀₆N—C(NR₂₀₅)—O—, R₂₀₅R₂₀₆N—C(NH)—O—,R₂₀₅NH—C(N R₂₀₅)—O—, R₂₀₅NH—C(N H)—O—, R₂₀₅N═CH—O—, R₂₀₅N═C(R₂₀₆)—O—,R₂₀₅NH—C(S)—O—, R₂₀₅R₂₀₆N—C(S)—O—; and/or R₂₁₄ constitutes together withR₂₁₃ a group of OCF₂O, CF₂OCF₂, CF₂OCF₂O and CF₂CF₂O, which formstogether with the carbons they are attached to a five to six memberedring;
 12. The use of a compound of formula (I) according to claim 1 forcontrolling parasites in animals.